Method of using citric acid for the treatment of wrinkles

ABSTRACT

A method for visibly reducing a skin wrinkle by topically applying to the wrinkle citric acid or a topically salt thereof.

This application is a continuation, of application Ser. No. 08/089,101,filed Jul. 12, 1993, now U.S. Pat. No. 5,389,677, which is a divisionalof U.S. application Ser. No. 08/008,223, filed Jan. 22, 1993, nowabandoned which is a continuation of U.S. application Ser. No.07/812,858, filed on Dec. 23, 1991, which is a continuation of U.S.application Ser. No. 07/469,738, filed on Jan. 19, 1990 now abandoned,which is a continuation of U.S. application Ser. No. 06/945,680, filedon Dec. 23, 1986 now abandoned.

This invention relates generally to method and composition containinghydroxyacid or related compound for enhancing therapeutic effects ofcosmetic or pharmaceutical agent. As will be subsequently described indetail, we initially discovered that alpha hydroxy or keto acids andtheir derivatives were effective in the topical treatment of diseaseconditions such as dry skin, ichthyosis, eczema, palmar and plantarhyperkeratoses, dandruff, acne and warts.

We have now discovered that hydroxyacids or related compounds whereinincorporated into a therapeutic composition can substantially enhancetopical effects of cosmetic and pharmaceutical agents.

In our prior U.S. Pat. No. 3,879,537 entitled "Treatment ofIchthyosiform Dermatoes" we described and claimed the use of certainalpha hydroxy acids, alpha keto acids and related compounds for topicaltreatment of fish-scale like ichthyotic conditions in humans. In ourU.S. Pat. No. 3,920,835 entitled "Treatment of Disturbed Keratinization"we described and claimed the use of these certain alpha hydroxy acids,alpha keto acids and their derivatives for topical treatment ofdandruff, acne, and palmar and plantar hyperkeratosis.

In our prior U.S. Pat. No. 4,105,783 entitled "Treatment of Dry Skin: wedescribed and claimed the use of alpha hydroxy acids, alpha keto acidsand their derivatives for topical treatment of dry skin. In our recentU.S. Pat. No. 4,246,261 entitled "Additives Enhancing TopicalCorticosteroid Action" we described and claimed that alpha hydroxyacids, alpha keto acids and their derivatives, in small amounts couldgreatly enhance the therapeutic efficacy of corticosteroids in topicaltreatment of psoriasis, eczema, seborrheic dermatitis and otherinflammatory skin conditions.

In our more recent U.S. Pat. No. 4,363,815 entitled "Alpha Hydroxyacids, Alpha Keto acids and Their Use in Treating Skin Conditions: wedescribed and claimed that alpha hydroxy acids and alpha keto acidsrelated to or originating from amino acids, whether or not found inproteins, were effective in topical treatment of skin disordersassociated with disturbed keratinization or inflammation. These skindisorders include dry skin, ichthyosis, palmar and plantarhyperkeratosis, dandruff, Darier's disease, lichen simplex chronicus,keratoses, acne, psoriasis, eczema, pruritus and possibly warts andherpes.

In our most recent U.S. Pat. No. 4,518,789 entitled "PhenylAlpha-Acyloxyacetamide Derivatives and Their Therapeutic Use" wedescribed and claimed that phenyl alpha acyloxyacetamide derivatives intopical or systemic administration were useful and effective forpruritus, atopic dermatitis, eczema, psoriasis, acne, dry skin,dandruff, malodors of integumental areas, various aches, pains anddiscomforts of skin, joints and other body parts in humans and domesticanimals.

The intact skin of humans is a very effective barrier to many naturaland synthetic substances. Cosmetic and pharmaceutical agents may bepharmacologically effective by systemic administration, but many of themare much less or totally ineffective on topical application to the skin.Topical effectiveness of a pharmaceutical agent depends on two majorfactors a) Percutaneous absorption and penetration b) Bioavailability ofthe penetrated pharmaceutical agent to the target site in the skin. Tobe therapeutically effective as a topical agent a pharmaceutical drugmust penetrate the stratum corneum into the epidermal layers,distributed and bioavailable to the target sites for pharmacologicaction. Many pharmacologic agents can readily penetrate the skin butthey are not bioavailable to the target sites in the skin, thereforetherapeutic effect is minimal and ineffective.

It has now been discovered that hydroxyacids and related compoundsincluding those described or not described in our previous patents andadditional compounds can substantially enhance the therapeutic efficacyof cosmetic and pharmaceutical agents in topical treatment of cosmeticconditions, dermatologic disorders or other afflictions. Cosmetic andpharmaceutical agents may include any chemical substances natural orsynthetic, intended for topical application to the skin or itsappendages in human and animals. Some examples of cosmetic andpharmaceutical agents include age spots and keratoses removing agents,analgesics, anesthetics, antiacne agents, antibacterials, antiyeastagents, antifungal agents, antiviral agents, antiburn agents,antidandruff agents, antidermatitis agents, antipruritic agents,antiperspirants, antiinflammatory agents, antihyperkeratolytic agents,antidryskin agents, antipsoriatic agents, antiseborrheic agents,astringents, softeners, emollient agents, coal tar, bath oils, sulfur,rinse conditioners, foot care agents, fungicides, hair growth promoters,hair removers, keratolytic agents, moisturizer agents, powder, shampoos,skin bleaches, skin protectants, soaps, cleansers, antiaging agents,sunscreen agents, wart removers, wet dressings, vitamins, tanningagents, topical antihistamin agents, hormones, vasodilators, retinoids,bronchial dilators, topical cardiovascular agents and otherdermatologicals.

The enhancing compounds of the instant invention are hydroxycarboxylicacids and related compounds. There are three groups of suchhydroxyacids. The first is hydroxymonocarboxylic acids having thefollowing chemical structure:

    R.sub.1 (CR.sub.2 OH).sub.m (CH.sub.2).sub.n COOH

wherein R₁, R₂ =H, alkyl, aralkyl or aryl group of saturated orunsaturated, straight or branched chain or cyclic form, having 1 to 25carbon atoms.

m=1, 2, 3, 4, 5, 6, 7, 8 or 9

n=0 or a numerical number up to 23

When n=0 and m=1 or more, the hydroxymonocarboxylic acid is also calledaldonic acid. The name comes from a carbohydrate, aldose, which may beoxidized to aldonic acid by the oxidation of the aldehyde group inaldose to the carboyxlic group.

The hydroxymonocarboxylic acid may be present as a free acid, lactone,or salt form. The lactone form could be either inter or intramolecularlactone, however, most common ones are intramolecular lactones with aring structure formed by elimination of one or more water moleculesbetween a hydroxy group and the carboxylic group. Since thehydroxymonocarboxylic acids are organic in nature, they may form a saltor a complex with an inorganic or organic base such as ammoniumhydroxide, sodium or potassium hydroxide, or triethanolamine.

The hydroxymonocarboxylic acid and its related compounds may also existas stereoisomers such as D, L, and DL forms.

The typical alkyl, aralkyl and aryl groups for R₁ and R₂ include methyl,ethyl, propyl, isopropyl, benzyl and phenyl. The hydrogen atoms of theR₁ and R₂ and (CH₂)_(n) may be substituted by a nonfunctional elementsuch as F, Cl, Br, I, S or a radical such as a lower alkyl or alkoxy,saturated or unsaturated, having 1 to 9 carbon atoms. Representativehydroxymonocarboxylic acids are listed below:

1. 2-Hydroxyacetic acid (Glycolic acid)

R₁ =H, R₂ =H, m=1, n=0

2. 2-Hydroxypropanoic acid (Lactic acid)

R₁ =CH₃, R₂ =H, m=1, n=0

3. 2-Methyl 2-hydroxypropanoic acid (Methyllactic acid)

R₁ =CH₃, R₂ =CH₃, m=1, n=0

4. 2-Hydroxybutanoic acid

R₁ =C₂ H₅, R₂ =H, m=1, n=0

5. Phenyl 2-hydroxyacetic acid (Mandelic acid)

R₁ =C₆ H₅, R₂ =H, m=1, n=0

6. Phenyl 2-methyl 2-hydroxyacetic acid (Atrolactic acid)

R₁ =C₆ H₅, R₂ =CH₃, m=1, n=0

7. 3-Phenyl 2-hydroxypropanoic acid (Phenyllactic acid)

R₁ =C₆ H₅, R₂ =H, m=1, n=1

8. 2,3-Dihydroxypropanoic acid (Glyceric acid)

R₁ =H, R₂ =H, m=2, n=0

9. 2, 3, 4-Trihydroxybutanoic acid

R₁ =H, R₂ =H, m=3, n=0

10. 2, 3, 4, 5-Tetrahydroxypentanoic acid

R₁ =H, R₂ =H, m=4, n=0

11. 2, 3, 4, 5, 6-Pentahydroxyhenxanoic acid

R₁ =H, R₂ =H, m=5, n=0

12. 2-Hydroxydodecanoic acid (alpha hydroxylauric acid)

R₁ =C₁₀ H₂₁, R₂ =H, m=1, n=0

13. 2, 3, 4, 5, 6, 7-Hexahydroxyheptanoic acid

R₁ =H, R₂ =H, m=6, n=0

14. Diphenyl 2-hydroxyacetic acid (benzilic acid)

R₁ =C₆ H₅, R₂ =C₆ H₅, m=1, n=0

15. 4-Hydroxymandelic acid

R₁ =C₆ H₄ (OH), R₂ =H, m=1, n=0

16. 4-Chloromandelic acid

R₁ =C₆ H₄ (Cl), R₂ =H, m=1, n=0

17. 3-Hydroxybutanoic acid

R₁ =CH₃, R₂ =H, m=1, n=

18. 4-Hydroxybutanoic acid

R₁ =H, R₂ =H, m=a, n=2

19. 2-Hydroxyhexanoic acid

R₁ =C₄ H₉, R₂ =H, m=1, n=0

20. 5-Hydroxydodecanoic acid

R₁ =C₇ H₁₅, R₂ =H, m=1, n=3

21. 12-Hydroxydodecanoic acid

R₁ =H, R₂ =H, m=1, n=10

22. 10-Hydroxydecanoic acid

R₁ =H, R₂ =H, m=1, n=8

23. 16-Hydroxyhexadecanoic acid

R₁ =H, R₂ =H, m=1, n=14

24. 2-Hydroxy-3-methylbutanoic acid

R₁ =C₃ H₇, R₂ =H, m=1, n=0

25. 2-Hydroxy-4-methylpentanoic acid

R₁ =C₄ H₉, R₂ =H, m=1, n=0

26. 3-Hydroxy-4-methoxymandelic acid

R₁ =C₆ H₃ (OH) (OCH₃), R₂ =H, m=l, n=0

27. 4-Hydroxy-3-methoxymandelic acid

R_(=C) ₆ H3 (OH) (OCH₃ ) , R₂ =H, m=1, n=0

28. 2-Hydroxy-2-methylbutanoic acid R₁ =C₂ H₅, R₂ =CH₃, m=1, n=0

29. 3-(2-Hydroxyphenyl) lactic acid

R₁ =C₆ H₄ (OH) CH₂, R₂ =H, m=1, n=0

30. 3-(4-Hydroxyphenyl) lactic acid

R₁ =C₆ H₄ (OH) CH₂, R₂ =H, m=1, n=0

31. Hexahydromandelic acid

R₁ =C₆ H₁₁, R₂ =H, m=1, n=0

32. 3-Hydroxy-3-methylpentanoic acid

R₁ =C₂ H₅, R₂ --CH₃, m=1, n=1

33. 4-Hydroxydecanoic acid

R₁ =C₆ H₁₃, R₂ =H, m=1, n=2

34. 5-Hydroxydecanoic acid

R₁ =C₅ H₁₁, R₂ =H, m=1, n=3

35. Aleuritic acid

R₁ =C₆ H₁₂ (OH), R₂ =H, m=2, n=7

The linear lactic acid polymer is an intermolecular lactone formed byelimination of one water molecule between the hydroxy group of onemolecule of lactic acid and the carboxylic group of a second molecule oflactic acid. The common linear lactic acid polymer may contain 3 lacticacid units.

Ribonic acid is one of the stereoisomers of 2, 3, 4,5-tetrahydroxypentanoic acid, and the corresponding lactone isribonolactone. Gluconic acid, galactonic acid, gulonic acid and mannonicacid are typical 2, 3, 4, 5, 6-pentahydroxyhexanoic acids and theircorresponding lactones are gluconolactone, galactonolactone,gulonolactone and mannonolactone respectively. The related compounds ofhydroxymonocarboxylic acids are ketomonocarboxylic acids which areformed from the former by a oxidation reaction or in vivo by adehydrogenase enzyme. For example, 2-ketopropanoic acid (pyruvic acid)and 2-hydroxypropanoic acid (lactic acid) are converted to each other invivo by the enzyme, lactate dehydrogenase. Although pure pyruvic acid(liquid form) can be kept in a refrigerator for an extended period oftime a composition containing pyruvic acid for topical use is not verystable at an elevated temperature. Therefore, for practical purposespyruvic acid esters are used instead.

The representative esters are methyl pyruvate, ethyl pyruvate, propylpyruvate and isopropyl pyruvate. Other representative ketomonocarboxylicacids and their esters are phenyl pyruvic acid and its esters such asmethyl phenyl pyruvate, ethyl phenyl pyruvate and propyl phenylpyruvate; formyl formic acid (2-ketoacetic acid) and its esters such asmethyl, ethyl and propyl formyl formate; benzoyl formic acid and itsesters such as methyl, ethyl and propyl benzoyl formate;4-hydroxybenzoylformic acid and its esters; 4-hydroxyphenylpyruvic acidand its esters; 2-hydroxyphenylpyruvic acid and its esters.

Many hydroxy or ketomonocarboxylic acids are structurally related toamino acids either naturally occurring in proteins or not. For examplealanine and pyruvic acid are interconverted to each other in vivo by anenzyme alanine dehydrogenase or alanine ketoglutarate transaminase. Asmentioned earlier pyruvic acid and lactic acid are interconverted toeach other in vivo by the enzyme lactate dehydrogenase. Therefore,alanine, pyruvic acid and lactic acid are chemically related in that theamino group of alanine may be converted to the keto group of pyruvicacid or the hydroxy group of lactic acid. The same relationships mayapply to formyl formic acid and glycolic acid to glycine; hydroxpyruvicacid and glyceric acid to serine; phenyl pyruvic acid and phenyl lacticacid to phenylalanine; 2-keto- and 2-hydroxy-4 (methylthio) butanoicacids to methionine.

The second kind of hydroxyacid is hydroxydicarboxylic acid having thefollowing chemical structure: ##STR1## wherein m=1, 2, 3, 4, 5, 6, 7, 8or 9

n=0 or a numerical number up to 23

The hydroxydicarboxylic acid may also be present as a free acid, lactoneor salt form. The lactone form could be either inter or intramolecularlactone. However, the common lactone is an intramolecular lactone with aring structure formed by elimination of one or more water moleculebetween a hydroxy group and one of the carboxylic groups. Since thehydroxydicarboxylic acid is organic in nature, it may form a salt or acomplex with an inorganic or organic base such as ammonium hydroxide.sodium or potassium hydroxide, or triethanolamine.

The hydroxydicarboxylic acid and its related compounds may also exist asstereoisomers such as D, L, DL and meso forms.

The hydrogen atom attached to the carbon atom may be substituted by anonfunctional element such as F, Cl, Br, I, S or a radical such as alower alkyl or alkoxy of saturated or unsaturated, having 1 to 9 carbonatoms.

When n=0 and m=1 or more, the hydroxydicarboxylic acid is also calledaldaric acid. The name comes from the carbohydrate, and the common onesare saccharic acid and galactaric acid. Representativehydroxydicarboxylic acids are listed below:

1. 2-Hydroxypropanedioic acid (Tartronic acid)

m=1, n=0

2. 2-Hydroxybutanedioic acid (Malic acid)

m=1, n=1

3. Erythraric acid and Threaric acid (Tartaric acid)

m=2, n=0

4. Arabiraric ,acid, Ribaric acid, Xylaric acid and Lyxaric acid

m=3, n=0

5. Glucaric acid (saccharic acid), Galactaric acid (Mucic acid),Mannaric acid, Gularic acid, Allaric acid, Altraric acid, Idaric acidand Talaric acid

m=4, n=0

Commercially available saccharolactone (D-saccharic acid 1, 4-lactone)is an intramolecular lactone formed by elimination of one water moleculebetween the hydroxy group at position 4 and the carboxylic group atposition 1.

The third type of hydroxyacid is a miscellaneous group of compoundswhich is not readily represented by the above generic structure ofeither the first type or the second type. Included in the third type ofhydroxyacids are the following:

Hydroxycarboxylic acid of

    R (OH).sub.m (COOH).sub.n

Wherein

m,n=1,2,3,4,5,6,7,8, or 9

R=H, alkyl, aralkyl or aryl group of saturated or unsaturated, straightor branched chain or cyclic form, having 1 to 25 carbon atoms.

citric acid, isocitric acid, citramalic acid, agaricic acid(n-hexadecylcitric acid), quinic acid, uronic acids including glucuronicacid, glucuronolactone, galacturonic acid, galacturonolactone,hydroxypyruvic acid, hydroxypyruvic acid phosphate, ascorbic acid,dihydroascorbic acid, dihydroxytartaric acid, 2-hydroxy-2-methylbutanoicacid, 1-hydroxy-1-cyclopropane carboxylic acid, 2-hydroxyhexanedial,5-hydroxylysine, 3-hydroxy-2-aminopentanoic acid, tropic acid,4-hydroxy-2, 2-diphenylbutanoic acid, 3-hydroxy-3-methylglutaric acid,and 4-hydroxy-3-pentenoic acid.

The third type of hydroxyacid may also be present as a free acid,lactone or salt form. The lactone form could be either an inter orintramolecular lactone, however, most common are intramolecular lactoneswith a ring structure. Commonly known glucuronolactone is a r-lactonei.e. 1,4-lactone of intramolecular type.

The hydroxyacid of the third type may also exist as stereoisomers suchas D, L, DL and meso forms. The hydrogen atom attached to the carbonatom may be substituted by a nonfunctional element such as F, Cl, Br, I,S or a radical such as a lower alkyl or alkoxy of saturated orunsaturated, having 1 to 9 carbon atoms.

Any hydroxyacid and related compound of the above three kinds may beused as an additive in a combination composition to enhance thepercutaneous penetration or the therapeutic efficacy of cosmetic andpharmaceutical agents. The cosmetic and pharmaceutical agents mayinclude but not limited to: age spots and keratoses removing agents,vitamins, aloes, retinoids, sun screens; tanning, depigmenting andshampooing agents; antiperspirants, antiyeasts, antifungal,antibacterial and antiviral agents; topical bronchial dilators; topicalcardiovascular agents; keratoses, age spots and wrinkles removal agents,hair growth promoting agents and other dermatological agents.

Hydroxyacids and related compounds may also be used alone in theprophylactic and therapeutic treatment of cosmetic conditions ordermatologic disorders characterized by disturbed keratinization, aging,lipid metabolism or inflammation. The representative hydroxyacids arelisted below:

citramalic acid, tropic acid, benzilic acid, ribonic acid andribonolactone, gulonic acid and gulonolactone, 2,3,4-trihydroxybutanoicacid, 2,3,4,5-tetrahydroxypentanoic acid, 2,3,4,5,6-pentahydroxyhexanoicacid, 2-hydroxylauric acid, 2,3,4,5,6,7-hexahydroxyheptanoic acid,aleuritic acid, 4-hydroxymandelic acid, 4-chloromandelic acid,2-hydroxy-3-methylbutanoic acid, 2-hydroxy-4-methylpentanoic acid,3-hydroxy-3-methylbutanoic acid, 2-hydroxy-4-methylpentanoic acid,3-hydroxy-4-methoxymandelic acid, 4-hydroxy-3-methoxymandelic acid,3-(2-hydroxyphenyl) lactic acid, 3-(4-hydroxyphenyl) lactic acid,hexahydromandelic acid, 3-hydroxy-3-methylpentanoic acid,1-hydroxy-l-cyclopropane carboxylic acid, 4-hydroxybutanoic acid,2-hydroxyhexanoic acid, 5-hydroxylauric acid, 12-hydroxylauric acid,10-hydroxydecanoic acid, 16-hydroxyhexadecanoic acid, 4-hydroxydecanoicacid, 5-hydroxydecanoic acid, and 4-hydroxy-2, 2-diphenylbutanoic acid.

Preparation of the Therapeutic Compositions

To prepare a therapeutic composition in solution form at least one ofthe aforementioned enhancing compounds of hydroxyacids and a cosmetic orpharmaceutical agent are dissolved in a solution which may consist ofethanol, water, propylene glycol, acetone or other pharmaceuticallyacceptable vehicles. The concentration of hydroxyacids may range from0.01 to 99 percent by weight of the total composition. The concentrationof the cosmetic or pharmaceutical agent ranges from 0.01 to 40 percentby weight of the total composition.

In the preparation of a therapeutic composition in cream or ointmentform at least one of hydroxyacids and one of cosmetic or pharmaceuticagents are initially dissolved in a solvent such as water, ethanol,acetone, propylene glycol or polysorbate 80. the solution thus preparedis then mixed in a conventional manner with commonly available cream orointment base such as hydrophilic ointment or petrolatum. Theconcentrations of hydroxyacids, cosmetic and pharmaceutical agents mayrange from 0.01 to 99 percent by weight of the total composition.

Therapeutic compositions of the instant invention may also be formulatedin gel, lotion, shampoo, spray, stick or powder. A typical gelcomposition of the instant invention utilizes at least one ofhydroxyacids and one of cosmetic or pharmaceutical agents dissolved in amixture of ethanol, water and propylene glycol in a volume ratio of40:40:20, respectively. A gelling agent such as hydroxyethylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose or ammoniatedglycyrrhizinate is then added to the mixture with agitation. Thepreferred concentration of the gelling agent may range from 0.1 to 4percent by weight of the total composition.

The following are illustrative examples of formulations and compositionsaccording to this invention. Although the examples utilize only selectedcompounds and formulations, it should be understood that the followingexamples are illustrative and not limitative. Therefore, any of theaforementioned hydroxyacids, cosmetic and pharmaceutical agents may besubstituted according to the teachings of this invention in thefollowing examples.

Example 1

A prophylactic and therapeutic composition in solution form for agespots and for keratoses may be prepared as follows.

Malic acid 1 gram, gluconolactone 19 grams and citric acid 0.5 gram aredissolved in a mixture of ethanol 30 ml, Water 42 ml and glycerin 5 ml.Sodium bisulfite 0.5 g and hydroquinone 2 grams are added with stirringuntil a clear solution is obtained. The hydroxyacids, malic acid,gluconolactone and citric acid have been added a) as antioxidants tohelp stabilize the hydroquinone in the composition b) to enhance thepenetration and the efficacy of hydroquinone c) to normalize thedisturbed keratinization in age spot and keratoses.

The composition thus formulated contains 2% hydroquinone, 1% malic acid,19% gluconolactone, 0.5% citric acid, and has pH 3.3

Example 2

A therapeutic composition in solution form for age spots and forkeratoses may be formulated as follows.

Alpha hydroxyisobutyric acid (Methyllactic acid) 20 grams and citricacid 2 grams are dissolved in a mixture of ethanol 49 ml, water 20 mland propylene glycol 7 ml. Sodium bisulfite 0.5 g and hydroquinone 2grams are added with stirring until a clear solution is obtained. Thecomposition thus formulated contains 2% hydroquinone, 2% citric acid,20% methyllactic acid, and has pH 3.6.

Example 3

A prophylactic and therapeutic composition containing minoxidil andlactic acid for hair growth and for prevention of hair loss on the scalpmay be formulated as follows.

Minoxidil 2 grams and lactic acid 3 ml are dissolved in a mixture ofethanol 80 ml and propylene glycol 15 ml with stirring until a clearsolution is obtained. The composition thus formulated contains 2%minoxidil, 3% lactic acid, and has pH 4.7. The lactic acid has beenadded to help minoxidil dissolved into solution, to enhance thepenetration and the efficacy of minoxidil for hair growth.

Example 4

A prophylactic and therapeutic composition in solution form for hairgrowth on the scalp may be formulated as follows.

Minoxidil 2 grams and ethyl pyruvate 2 ml are dissolved in a mixture ofethanol 80 ml and propylene glycol 16 ml. The composition thusformulated contains 2% minoxidil, 2% ethyl pyruvate, and has pH 5.0. Theketoacid ester, ethyl pyruvate has been added to enhance the penetrationand the efficacy of minoxidil for hair growth on the scalp.

Example 5

A therapeutic composition containing anthralin and hydroxyacid forpsoriasis may be formulated as follows.

Anthralin powder 0.5 gram and alpha hydroxyisobutyric acid 4 grams aredissolved in a mixture of ethanol 50 ml, acetone 30 ml and diisopropyladipate 16 ml with stirring until a clear yellowish solution isobtained. The composition thus formulated contains 0.5% anthralin, 4%alpha hydroxyisobutyric acid, and has pH 4.2. The hydroxyacid has beenadded to enhance the penetration and the efficacy of anthralin forpsoriasis.

Example 6

A therapeutic composition containing thionicotinamide and hydroxyacidfor psoriasis, keratoses and warts may be formulated as follows.

Thionicotinamide 2 grams and lactic acid 20 ml are dissolved in amixture of ethanol 40 ml, water 30 ml and propylene glycol 8 ml withstirring until a clear yellowish solution is Obtained. The compositionthus formulated contains 2% thionicotinamide, 20% lactic acid, and haspH 3.3. The lactic acid has been added to enhance the penetration andthe efficacy of thionicotinamide, and also to normalize the disturbedkeratinization in psoriasis, keratoses and warts.

Example 7

A therapeutic composition containing 6-aminonicotinamide and hydroxyacidfor psoriasis, keratoses and warts may be formulated as follows.

6-Aminonicotinamide 1 gram and glycolic acid 19 grams are dissolved in amixture of ethanol 40 ml, water 32 ml and propylene glycol 8 ml withstirring until a clear solution is obtained. The composition thusformulated contains 1% 6-aminonicotinamide, 19% glycolic acid, and haspH 3.0. The glycolic acid has been added to enhance the penetration andthe efficacy of 6-Aminonicotinamide, and also to normalize the disturbedkeratinization in psoriasis, keratoses and warts.

Example 8

A therapeutic composition containing clotrimazole and hydroxyacid forfungal infection may be formulated as follows.

Clotrimazole 1 gram and lactic acid 4 ml are dissolved in 4 ml ofethanol, and the solution thus obtained is mixed with 91 grams ofhydrophilic ointment USP. The mixing is continued until a uniformconsistency is obtained. The composition thus formulated contains 1%clotrimazole, 4% lactic acid, and has pH 3.2. The lactic acid has beenadded to enhance the penetration and the efficacy of clotrimazole forathlete's foot, and also to speed up healing and normalize the disturbedkeratinization.

Example 9

A prophylactic and therapeutic composition containing chlorhexidine andhydroxyacid as general antiseptics on skin, and for prophylactic andtherapeutic treatment of acne may be formulated as follows.Chlorhexidine diacetate 1 gram and benzilic acid 5 grams are dissolvedin a mixture of ethanol 70 ml, water 10 ml and propylene glycol 14 mlwith stirring until a clear solution is obtained. The composition thusformulated contains 1% chlorhexidine, 5% benzilic acid, and has pH 4.4.Benzilic acid has been added to enhance the antibacterial effect ofchlorhexidine, to eliminate the oiliness of the skin, and to improve theacne lesions.

Example 10

A prophylactic and therapeutic composition containing benzilic acid asthe only active ingredient for oily skin, acne, skin cleansing and skinmalodor may be formulated as follows.

Benzilic acid 7 grams is dissolved in a mixture of ethanol 60 ml, water20 ml and propylene glycol 13 ml with stirring until a clear solution isobtained. The composition thus prepared contains 7% benzilic acid, andhas pH 3.0.

Example 11

A therapeutic composition containing tropic acid as the only activeingredient for severe dry skin may be formulated as follows.

Tropic acid 10 grams is dissolved in 20 ml of ethanol, and the solutionthus obtained is mixed with 70 grams of hydrophilic ointment USP. Themixing is continued until a uniform consistency is obtained. Thecomposition thus formulated contains 10% tropic acid as an activeingredient, and has pH 3.7.

Example 12

A prophylactic and therapeutic composition containing ribonolactone asthe only active ingredient for oily skin, acne and skin cleansing may beformulated as follows.

Ribonolactone 4 grams is dissolved in a mixture of ethanol 36 ml andwater 60 ml with stirring until a clear solution is obtained. Thecomposition thus prepared contains 4% ribonolactone as an activeingredient, and has pH 3.8.

Example 13

A therapeutic composition containing hydrocortisone and tropic acid forinflammatory and/or pruritic skin disorders may be formulated asfollows.

Hydrocortisone 0.5 gram and tropic acid 5 grams are dissolved in 10 mlof ethanol and 4 ml of acetone, and the solution thus obtained is mixedwith 80 grams of hydrophilic ointment USP. The mixing is continued untila uniform consistency is obtained. The composition thus formulatedcontains 0.5% hydrocortisone and 5% tropic acid as active ingredients,and has pH 3.4. The tropic acid has been added to enhance thepenetration and the efficacy of hydrocortisone and also to normalize thedisturbed keratinization.

Example 14

A therapeutic composition containing triamcinolone acetonide andbenzilic acid for eczema, psoriasis and other inflammatory and pruriticskin disorders may be formulated as follows.

Triamcinolone acetonide 0.1 gram and benzilic acid 5 grams are dissolvedin 10 ml of ethanol, and the solution thus obtained is mixed with 85grams of hydrophilic ointment USP. The mixing is continued until auniform consistency is obtained. The composition thus formulatedcontains 0.1% triamcinolone acetonide, 5% benzilic acid, and has pH 3.4.The benzilic acid has been added to enhance the penetration and theefficacy of triamcinolone acetonide, and also to normalize the disturbedkeratinization in eczema, psoriasis and other inflammatory skindisorders.

Example 15

A prophylactic and therapeutic composition containing dipyridamole andlactic acid for hair growth and for prevention of hair loss on the scalpmay be formulated as follows.

Dipyridamole 2 grams and lactic acid 4 ml are dissolved in a mixture ofethanol 80 ml and propylene glycol 14 ml with stirring until a clearyellowish solution is obtained. The composition thus formulated contains2% dipyridamole, 4% lactic acid, and has pH 4.4. The lactic acid hasbeen added to help dipyridamole dissolved into solution, to enhance thepenetration and the efficacy of dipyridamole for hair growth and forpreventing hair loss.

Example 16

A therapeutic composition containing clobetasol propionate and agaricicacid for eczema, psoriasis and other inflammatory and pruritic skindisorders may be formulated as follows.

Agaricic acid fine powder 2 grams and 98 grams of clobetasol propionatecream are mixed until a uniform consistency is obtained. the compositionthus formulated contains approximately 0.05% clobetasol propionate, 2%agaricic acid, and has pH 4.3. The agaricic acid has been added toenhance the penetration and the efficacy of clobetasol propionate, andalso to normalize the disturbed keratinization in eczema, psoriasis andother inflammatory skin disorders.

Example 17

A therapeutic composition containing betamethasone dipropionate andbenzilic acid for eczema, psoriasis, contact dermatitis and otherinflammatory and pruritic skin disorders may be formulated as follows.

Benzilic acid powder 5 grams and 95 grams of betamethasone dipropionateointment are mixed until a uniform consistency is obtained. thecomposition thus formulated contains approximately 0.05% betamethasonedipropionate and 5% benzilic acid. The benzilic acid has been added toenhance the penetration and the efficacy of betamethasone dipropionate,and also to normalize the disturbed keratinization in eczema, psoriasisand other inflammatory skin disorders.

Example 18

A prophylactic and therapeutic composition containing aloe, malic acidand gluconolactone for oily skin and acne may be formulated as follows.

Aloe powder 200 fold 0.2 gram and ammoniated glycyrrhizinate 2 grams aremixed with water 61 ml and propylene glycol 2 ml. The mixture is heatedto 50° C. until the aloe powder and the ammoniated glycyrrhizinate arecompletely dissolved. Ethanol 10 ml is added to the solution followed bythe addition of partially neutralized malic acid stock solution 3 ml andgluconolactone stock solution 22 ml with stirring. The warm solution ispoured into container jars before cooling. The gel composition thusformulated contains 40% aloe, 1% malic acid, 9% gluconolactone, and haspH 4.0. Malic acid and gluconolactone have been added to enhance theskin softness and smoothness by aloe, and also to normalize anydisturbed keratinization of the skin.

Example 19

A sun screen composition containing Octyl dimethyl PABA, dioxybenzoneand lactic acid may be formulated as follows. Octyl dimethyl PABA 5grams, dioxybenzone 3 grams and lactic acid 2 ml are dissolved in amixture of ethanol 65 ml, water 10 ml and propylene glycol 15 ml withstirring until a clear solution is obtained. The composition thusformulated contains 5% octyl dimethyl PABA, 3% dioxybenzone, 2% lacticacid, and has pH 3.6. The lactic acid has been added to substantiate theabsorption of sunscreen agents, octyl dimethyl PABA and dioxybenzone,and to enhance the sun screen effect.

Example 20

A prophylactic and therapeutic composition containing tetracycline andglycolic acid for oily skin and-acne may be formulated as follows.

Tetracycline 3 grams and glycolic acid 5 grams are dissolved in amixture of ethanol 40 ml, water 40 ml and propylene glycol 12 ml withstirring until the tetracycline and glycolic acid are completelydissolved. The composition thus formulated contains 3% tetracycline, 5%glycolic acid, and has pH 3.4. The glycolic acid has been added to helptetracycline dissolved into the solution, to enhance the penetration andthe efficacy of tetracycline, and to normalize the disturbedkeratinization in acne.

Example 21

A therapeutic composition containing griseofulvin and methyl pyruvatefor fungal infection of nails may be formulated at follows.

Griseofulvin 1 gram and methyl pyruvate 2 ml are dissolved in a mixtureof 2-pyrrolidone 20 ml. PEG-400 47 ml and ethanol 30 ml with stirringuntil the griseofulvin is completely dissolved. The composition thusformulated contains 1% griseofulvin, 2% methyl pyruvate, and has pH 4.4.The methyl pyruvate has been added to help griseofulvin dissolve intothe solution, to enhance the penetration and the efficacy ofgriseofulvin, and to normalize the disturbed keratinization in nails.

Example 22

A therapeutic composition containing lidocaine and atrolactic acid forpruritic skin may be formulated as follows.

Lidocaine 2 grams and atrolactic acid hemihydrate 3 grams are dissolvedin a mixture of ethanol 40 ml, water 40 ml and propylene glycol 15 mlwith stirring until the lidocaine and atrolactic acid are completelydissolved. The composition thus formulated contains 2% lidocaine, 3%atrolactic acid, and has pH 4.6. The atrolactic acid has been added tohelp lidocaine dissolved and stabilized in the solution and to enhancethe efficacy of lidocaine for pruritic skin.

Example 23

A prophylactic and therapeutic composition containing retinoic acid andethyl pyruvate for oily skin and acne may be formulated as follows.

Retinoic acid, all-trans 0.1 gram and ethyl pyruvate 2 ml are dissolvedin a mixture of ethanol 80 ml, water 10 ml and propylene glycol 8 mlwith stirring until a yellowish solution is obtained. The compositionthus formulated contains 0.1% vitamin A acid, 2% ethyl pyruvate, and haspH 3.6. The ethyl pyruvate has been added to enhance the penetration andthe efficacy of retinoic acid, and to normalize the disturbedkeratinization in acne.

Example 24

A prophylactic and therapeutic composition containing erythromycin andaleuritic acid for oily skin and acne may be formulated as follows.

Erythromycin 2 grams and aleuritic acid 2 grams are dissolved in amixture of ethanol 50 ml, water 40 ml and propylene glycol 6 ml withstirring until a clear solution is obtained. The composition thusformulated contains 2% erythromycin, 2% aleuritic acid, and has pH 5.7.The aleuritic acid has been added to help erythromycin dissolve into thesolution, to enhance the penetration and the efficacy of erythromycin,and to normalize the disturbed keratinization in acne.

Example 25

A therapeutic composition containing P-hydroxymandelic acid for dry skinmay be formulated as follows.

P-Hydroxymandelic acid 10 grams is dissolved in 20 ml of ethanol, andthe pinkish solution thus obtained is mixed with 70 grams of hydrophilicointment USP with stirring until a uniform consistency is obtained. Thecomposition thus formulated contains 10% P-hydroxymandelic acid as anactive ingredient, and has pH 3.2. P-Hydroxymandelic acid has beenincorporated into the composition to alleviate any scaly or flaky skin,and to change the dry skin into normal smooth and soft skin.

Example 26

A therapeutic composition containing hydroquinone and lactic acid insolution form for age spots, keratoses, melasmas, lentigines and otherpigmented skin spots may be formulated as follows.

Lactic acid 10 ml, hydroquinone 4 grams and sodium metabisulfite 0.6gram are dissolved in a mixture of ethanol 70 ml, water 10 ml andpropylene glycol 6 ml with stirring until a clear solution is obtained.The composition thus formulated contains 4% hydroquinone, 10% lacticacid, and has pH 4.0. The lactic acid has been added to help stabilizeand enhance the penetration and the efficacy of hydroquinone, and alsoto normalize the disturbed keratinization in the skin lesions. Thecomposition thus formulated is packaged in felt pens for controlleddelivery to skin lesions.

Example 27

A therapeutic composition, containing hydroquinone and glycolic acid insolution form for age spots, keratoses, melasmas, lentigines and otherpigmented skin spots may be formulated as follows.

Glycolic acid 8 grams, hydroquinone 5 grams and sodium metabisulfite 0.5gram are dissolved in a mixture of ethanol 70 ml, water 10 ml andpropylene glycol 7 ml with stirring until a clear solution is obtained.The composition thus formulated contains 5% hydroquinone, 8% glycolicacid, and has pH 3.9. The glycolic acid has been added to help stabilizeand enhance the penetration and the efficacy of hydroquinone, and alsoto normalize the disturbed keratinization in the skin lesions. Thecomposition thus prepared is packaged in felt pens for controlleddelivery to skin lesions.

Example 28

A therapeutic composition containing hydroquinone and 2-methyl2-hydroxypropanoic acid in solution form for age spots, keratoses,melasmas, lentigines and other pigmented skin spots may be formulated asfollows.

2-Methyl 2-hydroxypropanoic acid 12 grams, hydroquinone 4 grams andsodium bisulfite 0.3 gram are dissolved in a mixture of ethanol 60 ml,water 20 ml and propylene glycol 4 ml with stirring until a clearsolution is obtained. The composition thus formulated contains 4%hydroquinone, 12% 2-methyl 2-hydroxypropanoic acid, and has pH 4.0. Thecomposition solution is packaged in felt pens for controlled delivery toskin lesions. The 2-methyl 2-hydroxypropanoic acid has been added tohelp stabilize and enhance the penetration and the efficacy ofhydroquinone, and also to normalize the disturbed keratinization in theskin lesions.

Example 29

A composition containing hydroquinone alone in solution form for agespots and keratoses studies may be formulated as follows.

Hydroquinone 5 grams and sodium metal bisulfite 0.5 gram are dissolvedin a mixture of ethanol 70 ml, water 15 ml and propylene glycol 10 mlwith stirring until a clear solution is obtained. The composition thusprepared contains 5% hydroquinone and has pH 6.0. The compositionsolution is packaged in felt pens for comparative studies; with orwithout hydroxyacids on age spots and keratoses.

TEST RESULTS

In order to determine whether addition of a hydroxyacid in thecomposition could enhance the therapeutic action of a cosmetic orpharmaceutical agent a total of more than 55 volunteers and patientshaving different skin disorders participated in these studies. Eachparticipating subject was given two preparations; i.e. with or withoutthe addition of a hydroxyacid in the therapeutic composition.

Topical applications were carried out either by bilateral or sequentialcomparison, In bilateral comparison the subject was instructed to applyone preparation on one side of the body and the other one on the otherside of the body. For psoriasis, eczema, severe dry skin, athlete'sfoot, etc., where both sides were involved, the subject was instructedto apply two to three times daily one medication on one side of the bodyfor a period of up to several months of time. In the pulse treatment forpsoriasis or other inflammatory diseases the medication was applied onlyonce every three days or twice a week. The medication was discontinuedwhenever a total remission of the lesions occurred prior to the testperiod of up to several months.

For the scalp or face involvement such as in dandruff, oily skin, acneand seborrheic dermatitis the subject was instructed to apply two tothree time daily one medication on one side of the scalp or the face andthe other medication on the other side of the scalp or the face for aperiod of up to 12 weeks of time. For age spots, keratoses or warts themedication was continued for up to 4 months of time.

Sequential administrations of medications were carried out whenever thebilateral comparison was difficult. for example in pruritic conditionsthe subject was instructed to apply four time daily or as often asnecessary one medication on the pruritic lesions for two days, thenswitched to the other medication on the same lesions for another twodays, thus to compare which medication was more effective in relievingthe itching.

1. Dry skin.

Human subjects having ordinary dry skin or with moderate degrees of dryskin as evidenced by dry, flaking and cracking of the skin wereinstructed to apply topically the lotion, cream or ointment containing 3to 7 percent of hydroxyacids of the instant invention on the affectedskin areas. Topical application, two to three times daily, was continuedfor two to three weeks. In all the nine subjects tested, the feeling ofthe skin dryness disappeared within a week of topical application. Therough and cracked skin became less pronounced and the skin appearednormal and felt smooth after 10 days of topical treatment.

The ordinary dry skin conditions once restored to normal appearing skinremained improved for some time until causes of dry skin, such as lowhumidity,, cold weather, excessive contact pressure, detergents, soaps,solvents, chemicals, etc., again caused recurrence of the dry skincondition. On continued use it was also found that twice daily topicalapplication of a composition containing one or more hydroxyacids ofinstant invention prevented the development of new dry skin lesions.

In severe dry skin the skin lesions are different from the above. Theinvolved skin is hyperplastic, fissured and has thick adherent scales.The degree of thickening is such that lesions are palpably and visuallyelevated. The thickened adherent scales cause the surface of involvedskin to be markedly rough and uneven. The two attributes of thicknessand texture can be quantified to allow objective measurement of degreeof improvement from topically applied therapeutic test materials asfollows:

    __________________________________________________________________________    DEGREE OF IMPROVEMENT                                                                 None  Mild  Moderate                                                                             Substantial                                                                         Complete                                             (0)   (1+)  (2+)   (3+)  (4+)                                         __________________________________________________________________________    THICKNESS                                                                             Highly                                                                              Detectable                                                                          Readily                                                                              Barely                                                                              Normal                                               elevated                                                                            reduction                                                                           apparent                                                                             elevated                                                                            thickness                                                        reduction                                                 TEXTURE Visibly                                                                             Palpably                                                                            Uneven but                                                                           Slightly                                                                            Visibly and                                          rough rough not rough                                                                            uneven                                                                              palpably                                                                      smooth                                       __________________________________________________________________________

By means of such parameters degrees of change in lesions can benumerically noted and comparisons made of one treated site to another.

In order to evaluate the hydroxyacids and their related compounds of theinstant invention a total of six patients with severe dry skinconditions or ichthyosis were treated with the compositions containing 7to 15% of hydroxyacids as described in the Examples.

Treated areas were of a size convenient for topical applications, i.e.,circles 5 cm in diameter demarcated with a plastic ring of that sizeinked on a stamp pad. The medicinal creams or ointments were topicallyapplied by the patient in an amount sufficient to cover the treatmentsites. Applications were made three time daily and without occlusivedressings. Applications were discontinued at any time when resolution ofthe lesion on the treatment area was clinically judged to be complete.

The test results on patients with severe dry skin are summarized on thefollowing table.

    ______________________________________                                        Topical Effectiveness of Hydroxyacids on Severe Dry Skin                                         Number of Therapeutic                                      Compounds          Patients  Effectiveness                                    ______________________________________                                        1. Tropic acid     4         4+                                               2. Benzilic acid   5         4+                                               3. Ribonolactone   3         3+                                               4. 4-Hydroxymandelic acid                                                                        2         3+                                               5. 3-Chloro 4-hydroxymandelic acid                                                               2         3+                                               6. 3,4-Dihydroxymandelic acid                                                                    2         3+                                               ______________________________________                                    

2. Psoriasis

The involved skin in psoriasis is hyperplastic (thickened), erythematous(red or inflamed), and has thick adherent scales. the degree ofthickening is such that lesions are elevated up to 1 mm above thesurface of adjacent normal skin; erythema is usually an intense red; thethickened adherent scales cause the surface of involved skin to bemarkedly rough and uneven. These three attributes of thickness, colorand texture can be quantified to allow objective measurement of degreeof improvement from topically applied therapeutic test materials asfollows.

    __________________________________________________________________________    DEGREE OF IMPROVEMENT                                                         None       Mild  Moderate                                                                            Substantial                                                                          Complete                                        (0)        (1+)  (2+)  (3+)   (4+)                                            __________________________________________________________________________    Thickness                                                                           Highly                                                                             Detectable                                                                          Readily                                                                             Barely Normal                                                elevated                                                                           reduction                                                                           apparent                                                                            elevated                                                                             thickness                                       Texture                                                                             Visibly                                                                            Palpably                                                                            Uneven but                                                                          Slightly                                                                             Visibly and                                           rough                                                                              rough not rough                                                                           uneven palpably smooth                                 Color Intense                                                                            Red   Dark Pink                                                                           Light  Normal skin                                           red              pink   color                                           __________________________________________________________________________

By means of such parameters degree of improvements in psoriatic lesionscan be numerically recorded and comparisons made of one treated site toanother. The treatment schedule was quite different from the previouslydescribed in that the present study was employing a "Pulse Treatment."Instead of several times daily application the therapeutic compositionof antipsoriatic agent with or without a hydroxyacid in solution formwas topically applied to the involved skin only once in every three daysor twice a week. The test results on patients having psoriasis aresummarized on the following table.

    ______________________________________                                        Topical Effects on Psoriasis of Antipsoriatic Agents                          With or without Hydroxyacids                                                                      Number of Therapeutic                                     Compositions        Patients  Effectivenes                                    ______________________________________                                        Thionicotinamide 3% alone                                                                         6         2+                                              with 10% Lactic acid                                                                              6         4+                                              with 5% Glycolic acid                                                                             4         4+                                              with 5% 2-methyl    3         4+                                              2-hydroxyropanoic acid                                                        6-Aminonicotinamide 1% alone                                                                      5         3+                                              with 10% Lactic acid                                                                              5         4+                                              with 10% Glycolic acid                                                                            4         4+                                              Betamethasone dipropionate 0.05%                                                                  5         3+                                              ointment alone                                                                with 5% Benzilic acid                                                                             4         4+                                              with 5% Tropic acid 3         4+                                              with 5% 2-Methyl    3         4+                                              2-Hydroxyproanoic acid                                                        Clobetasol propionate 0.05%                                                                       4         2+                                              cream alone                                                                   with 5% Benzilic acid                                                                             3         3+                                              with 5% Tropic acid 2         3+                                              with 5% 2-Methyl    3         3+                                              2-hydroxyropanoic acid                                                        ______________________________________                                    

In a topical treatment of eczema patients, betamethasone dipropionate orclobetasol propionate alone at 0.05% would achieve only a 3+ improvementon all the eczema patients tested. As shown by the table with theadditional of 5% gluconolactone or ribonolactone betamethasonedipropionate or clobetasol propionate could attain a 4+ maximal clearingon all the eczema patients tested.

    ______________________________________                                        Topical Effects on Eczema of Corticosteroids                                  With and Without Hydroxyacid Lactone                                                              Number of Therapeutic                                     Composition         Patients  Effectivenes                                    ______________________________________                                        Betamethasone dipropionate 0.05%                                                                  3         3+                                              alone                                                                         with 5% Gluconolactone                                                                            3         4+                                              with 5% Ribonolactone                                                                             2         4+                                              Clobetasol propionate 0.05% alone                                                                 4         3+                                              with 5% Gluconolactone                                                                            4         4+                                              with 5% Ribonolactone                                                                             3         4+                                              ______________________________________                                    

3. Age Spots, Wrinkles, Keratoses and Pigmented Skin lesions.

Therapeutic compositions packaged in felt pens as described in Exampleswere provided to 14 patients for treatment of age spots, wrinkles,keratoses and other pigmented skin spots. Each participating patientreceived two felt pens; i.e. with or without the addition of hydroxyacidto the composition containing hydroquinone. The patients were instructedto apply topically one medication on one side of the body such as on theback of the left hand and the other medication on the other side of thebody such as on the back of the right hand. Specific instructions weregiven to the patients that the medications were applied twice daily anddiscretely only to the skin lesions of age spots, wrinkles, keratoses,melasmas, lentigines or other pigmented skin spots.

Within one to three weeks, improvement of age spots and keratoses wasclinically discernible. After one to three months substantialeradication of age spots, wrinkles and keratoses occurred in all thepatients tested. Complete eradication of age spots usually occurredwithin two to four months of topical administration in most cases.Therapeutic compositions containing higher concentrations ofhydroxyacids (10 to 20%) and hydroquinone (3 to 5%) were judged to bemore efficient in eradicating age spots, wrinkles and keratoses withinshorter periods of time. Without the addition of a hydroxyacid to thecomposition of hydroquinone, eradication of age spots, wrinkles orkeratoses did not occur within four months of time.

It was also found that while compositions containing hydroxyacidswithout hydroquinone were effective for eradication of keratoses andwrinkles, the compositions were not efficient in eradicating pigmentedage spots, melasmas or lentigines within 4 months of time. In any case,with the addition of a hydroxyacid to the composition containinghydroquinone, pigmented age spots, melasmas, lentigines and otherpigmented skin spots had been substantially eradicated.

4. Acne.

Therapeutic compositions containing tetracycline, erythromycin orchlorhexidine with or without the addition of a hydroxyacid wereprovided to 9 patients having papulopustular or pustular lesions ofacne. Each participating patient received two medications, with orwithout the addition of a hydroxyacid to the composition containing anantibiotic. The patients were instructed to apply topically onemedication on one side of the body such as the left side forehead, face,back or chest, and the other medication on the other side of the bodysuch as right side forehead, face, back or chest. Twice dailyadministration was continued for 4 to 12 weeks.

The degree and rate of improvement on acne lesions were clinicallyevaluated, and comparison was made between the two sides; one side withand the other side without a hydroxyacid in the compositions containingan antibiotic. It was found that the degree and rate of improvement onacne lesions were substantially better on the side treated with acombination composition containing both the hydroxyacid and theantibiotic as compared to that of the antibiotic alone. The time forcomplete clearing of acne lesions treated with a combination compositionvaried from 4 to 12 weeks of time, with an average time of 8 weeks,whereas complete clearing with that of the antibiotic alone ranged from8 weeks to 9 months, with an average of 4 months.

5. Preventing Hair Loss And For Hair Growth.

Prophylactic and therapeutic compositions containing minoxidil ordipyridamole with or without a hydroxyacid or related compound wereprovided to 6 human subjects having a progressive loss of hair on thescalp. Each participating subject received two medications; i.e. with orwithout the addition of a hydroxyacid to the composition containingminoxidil or dipyridamole. The subjects were instructed to applytopically one medication on one side of the scalp and the othermedication on the other side of the scalp. Twice daily topicalapplications were continued for 2 to 6 months. Clinical evaluation showsthat the combination compositions containing minoxidil or dipyridamoleand a hydroxyacid or related compound were therapeutically moreefficient in preventing the hair loss and enhancing hair growth on thescalp.

Therapeutic compositions containing clotrimazole or griseofulvin with orwithout the addition of a hydroxyacid were provided to 6 patients havingrecurrent fungal infections of the foot; i.e. athlete's foot with orwithout toe nail involvement. Each participating patient received twomedications with or without the addition of a hydroxyacid to thecomposition containing clotrimazole or griseofulvin. The patients wereinstructed to apply topically one medication on one side of the bodysuch as left foot, and the other medication on the other side of thebody such as right foot. Three time daily applications were continuedfor one to two weeks. When nail infections were involved the topicalapplication was continued for up to 4 months using the compositionscontaining griseofulvin with or without the addition of a hydroxyacid.

The degree and rate of improvement on skin lesions were clinicallyevaluated, and comparison was made one side of the body against theother. It was found that the skin lesions improved much faster with thecompositions containing both the antifungal agent and the hydroxyacid.The presence of hydroxyacid appeared to enhance the efficacy of theantifungal agent, and also to eliminate the discomforts such as itching,tingling, burning and heat due to the fungal infection. Generally theinfected skin healed within a week from topical application of thecompositions containing an antifungal agent and a hydroxyacid. When toenails were involved in the fungal infection the complete healing andregrowth of nails usually took several months on continued topicalapplication of medications containing griseofulvin and a hydroxyacid.

The hydroxyacids and related compounds which may be useful asdermatologic agents for various conditions and disorders including agespots, keratoses, skin wrinkles etc. or as additives to enhancetherapeutic effects of other cosmetic or pharmaceutical agents include2-Hydroxyacetic acid; 2-hydroxypropanoic acid; 2-methyl2-hydroxypropanoic acid; 2-hydroxybutanoic acid; phenyl 2-hydroxyaceticacid; phenyl 2-methyl 2-hydroxyacetic acid; 3-phenyl 2-hydroxyaceticacid; 2,3-dihyroxypropanoic acid; 2,3,4-trihydroxybutanoic acid;2,3,4,5,6-pentahydroxyhexanoic acid; 2-hydroxydodecanoic acid;2,3,4,5-tetrahydroxypentanoic acid; 2,3,4,5,6,7-hexahydroxyheptanoicacid; diphenyl 2-hydroxyacetic acid; 4-hydroxymandelic acid;4-chloromandelic acid; 3-hydroxybutanoic acid; 4-hydroxybutanoic acid;2-hydroxyhexanoic acid; 5-hydroxydodecanoic acid; 12-hydroxydodecanoicacid; 10-hydroxydecanoic acid; 16-hydroxyhexadecanoic acid;2-hydroxy-3-methylbutanoic acid; 2-hydroxy-4-methylpentanoic acid;3-hydroxy-4-methoxymandelic acid; 4-hydroxy-3-methoxymandelic acid;2-hydroxy-2-methylbutanoic acid; 3-(2-hydroxphenyl) lactic acid;3-(4-hydroxyphenyl) lactic acid; hexahydromandelic acid;3-hydroxy-3-methylpentanoic acid; 4-hydroxydecanoic acid;5-hydroxydecanoic acid; aleuritic acid.

2-Hydroxypropanedioic acid; 2-hydroxybutanedioic acid; erythraric acid;threaric acid; arabiraric acid; ribaric acid; xylaric acid; lyxaricacid; glucaric acid; galactaric acid; mannaric acid; gularic acid;allaric acid; altraric acid; idaric acid; talaric acid;2-hydroxy-2-methylbutanedioic acid.

Citric acid, isocitric acid agaricic acid, quinic acid, glucuronic acid,glucuronolactone, galacturonic acid, galacturonolactone, uronic acids,uronolactones, ascorbic acid, dihydroascorbic acid, dihydroxytartaricacid, tropic acid, ribonolactone, gluconolactone, galactonolactone,gulonolactone, mannonolactone, citramalic acid.

Pyruvic acid, hydroxypyruvic acid, hydroxypyruvic acid phosphate, theiresters; methyl pyruvate, ethyl pyruvate, propyl pyruvate, isopropylpyruvate; phenyl pyruvic acid, its esters; methyl phenyl pyruvate, ethylphenyl pyruvate, propyl phenyl pyruvate; formyl formic acid; its esters;methyl formyl formate, ethyl formyl formate, propyl formyl formate;benzoyl formic acid, its esters; methyl benzoyl formate, ethyl benzoylformate and propyl benzoyl formate; 4-hydroxybenzoyl formic acid, itsesters; 4-hydroxyphenyl pyruvic acid, its esters; 2-hydroxyphenylpyruvic acid and its esters.

The invention may be embodied in other specific forms without departingfrom the spirit or essential characteristics thereof. The presentembodiments are therefore to be considered in all respects asillustrative and not restrictive, the scope of the invention beingindicated by the appended claims and all changes which come within themeaning and equivalency of the claims are therefore intended to beembraced therein.

What is claimed is:
 1. Method of visibly reducing a human skin wrinklecomprising topically applying to said wrinkle citric acid, or atopically effective salt thereof, in an amount and for a period of timesufficient to visibly reduce said wrinkle.
 2. The method according toclaim 1, wherein said citric acid is in the form of a free acid.
 3. Themethod according to claim 1, wherein said citric acid is in salt form.4. The method according to claim 1, wherein said citric acid ortopically effective salt thereof is applied periodically for a period oftime sufficient to achieve at least a clinically discernable reductionof said wrinkle.
 5. The method according to claim 1, wherein said citricacid or topically effective salt thereof is applied periodically for aperiod of time sufficient to achieve at least a substantial eradicationof said wrinkle.
 6. The method according to claim 1, wherein said periodof time is at least three months.
 7. The method according to claim 1,wherein said period of time is at least four months.
 8. The methodaccording to claim 1, wherein said topical application is on a dailybasis.
 9. The method according to claim 1, wherein said citric acid ortopically effective salt thereof is present in a topically acceptablecomposition comprising a carrier.
 10. The method according to claim 9,wherein said composition is a lotion, cream, gel, ointment or solution.